Chapter 4BLOOD &

IMMUNE SYSTEM

I. BloodA. ErythrocytesB. PlateletsC. Leukocytes

II. Immune SystemA. Immunity

1. Non-Specific Immune Responses2. Specific Immune Response

B. Disorders of the Immune System

Goals: List the components of blood and their usual concentrations in a healthy adult Discuss the functions of the immune system List the types and functions of the five immunoglobulins Discuss the differences between specific and non-specific immune responses and give an example of

each. Discuss the differences between B and T-cells Briefly discuss how vaccination protects an individual from disease Differentiate between a primary and secondary immune response Describe two disorders of the immune system

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Immunology Related Terms to Know…

immunologist - a person who makes a special study of immunology, that branch of biomedical science concerned with the response of the organism to antigenic challenge, the recognition of non-self, and all the biological (in vivo) serological (in vitro) and physical chemical aspects of immune phenomena.

antigen - any substance, which is capable, under appropriate conditions, of including the formation of antibodies. Antigens may be soluble substances such as toxins and foreign proteins, or particulate, such as bacterial and tissue cells.

antibody - an Ig molecule tat has a specific amino acid sequence by virtue of which it interacts only with the antigen that induced its synthesis in lymphoid tissue, or with antigen closely related to it.

immunity humoral immunity - acquired immunity in which the role of circulatory antibodies (immunoglobulins) in predominant. This is most important for defense against most bacteria, viruses, and toxins. Important in most immune responses.

cellular immunity - specific acquired immunity in which the role of small lymphocytes of thymic origin is predominant it is responsible for resistance to infectious disease caused by certain bacteria (TB), protozoa (pneumocystis) and by viruses (CMV, herpes), certain aspects of resistance to cancer, delayed hypersensitivity reactions, certain autoimmune disease, and allograft rejection.

hypersensitivityimmediate hypersensitivity - a state of altered reactivity in which the body reacts with an exaggerated response to a foreign agent (most allergies). Antibody mediated characterized by lesions resulting from the release of histamine and other vasoactive substances (type 1 reaction - e.g. anaphylaxis).

delayed hypersensitivity - a slowly developing increase in cell-mediated immune response to a specific antigen; it is involved in the graft reaction phenomenon, autoimmune disease, and contact dermatitis (as in response to poison ivy).

immunoglobulins (Igs) - A protein of animal origin endowed with known antibody activity. Igs function as specific antibodies and are responsible for the humoral aspects of immunity. They are found in the serum and in other body fluids and tissues, including the urine, spinal fluid, lymph nodes, spleen, etc. Molecularly each Ig is made up to 2 light chains and 2 heavy chains, this basic 4 chain unit being repeated in the higher molecular weight forms, as in the pentameric IgM molecule. There are 5 antigenically different kinds of heavy chains, which form the basis of the 5 classes of Ig (IgA, IgD, IgE, IgG, IgM). IgA is the secretory antibody present in the bowel, saliva, tears, milk, mucus, and urine. Where it is absent, persons have many respiratory infections. IgE adheres to mast cells and basophils and is responsible to most allergy. IgG is the primary antibody in the serum.

T-cell - a type of lymphocytes important in immunity. It is chiefly a product of lymphoid tissue and participates in humoral and cell-mediated immunity. Thymus dependent cells must either pass through the thymus or are influenced by it on their way to the tissues; they can suppress or assist the stimulation of antibody production in B-lymphocytes in the presence of antigen, and can kill such cells as tumor and transplant tissue cells. They are thought to have a long life span and to be responsible for cell-mediated immunity and immunological memory. The AIDS virus suppresses the formation of T-cells.

B-cell - "bursa-equiv" lymphocytes (thymus - independent, migrating to the tissues without passing through or being influenced by they thymus). B-cells mature into plasma cells that synthesize humoral antibody.

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plasma cell - a spherical or ellipsoidal cell, with a single eccentrically placed nucleus containing clumped chromatin; they are functionally involved, under varying circumstances; in the synthesis of Ig and their components (plasma being the fluid portion of the blood in which the corpuscles are suspended).

thymus - a ductless gland-like body situated in the anterior mediastinal cavity, which reaches its maximum developed during the early years of childhood and then undergoes involution. It plays a role in immunologic competence.

Immunological responsesprimary response - the immune response to initial stimulation by an antigen' characterized by a latent period before the synthesis of specific antibody is begun.

secondary response - anamestic response - the rapid reappearance of antibody in the blood following the administration of an antigen to which the subject had previously developed a primary immune response, also called memory response.

immune complexes - antibody/antigen combination in bloodstream. When present in excess the may collect in the joints and the kidney.

in vitro - within a glass, observable in a test tube, in an artificial environment.

anaphylaxis - an unusual or exaggerated allergic reaction to foreign protein or other substances. Anaphylaxis is an antigen - antibody reaction.

atopy (allergy) - a clinical hypersensivitiy state, or allergy with a hereditary predisposition, that is, the tendency to develop some form of allergy is inherited, but the tendency to develop some form of allergy is inherited, but the specific clinical form is not. An unusual type of antibody, termed regain, which is in the IgE class, is involved.

urticaria (hives) - a vascular reaction of the skin marked by the transient appearance of smooth, slightly elevated patches (wheals) which are redder or paler than the surrounding skin and often attended by severe itching. The eruption seldom lasts more than 2 days, but may exist in a chronic form. Certain foods (e.g. shellfish), drugs (penicillin), infection or emotional stress may be the exciting cause.

immunosupression - the artificial prevention or diminution of the immune response, as by irradiation or by administration of antimetabolities, corticosteriods, antilymphocytic serum, or specific antibody.

histamine - an amine, formed by decarboxylation of histidine and occurring in many animal and vegetable tissues, also in the granules of mast cells and basophils. It has at least 3 important functions - dilation of capillaries, which increase capillary permeability and results in a drop in blood pressure - constriction of the bronchial smooth muscle of the lungs, and - induction of increased gastric secretion. It is also responsible for the triple response and is implicated as a mediator of immediate hypersensivitiy.

antihistamine - a drug that counteracts the effect of histamine.

mast cell - a connective tissue cell whose specific physiologic function remains unknown; capable of elaborating basophilic, metachromatic cytoplasmic granules containing histamine, heparin.

autoimmunity - a condition characterized by a specific humoral cell or cells - mediated immune response against the constituents of the body's own tissues (autoantigens); it may result in autoimmune diseases.

AIDS - a fatal disease caused by a virus which is transmitted through exchange of bodily fluids. May have a latent period of up to 9 years. The virus attacks T-cells among others, and the individual succumbs to opportunistic infections, often rare in people without AIDS.

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pruritis - itching; also the name of various conditions characterized by itching, the specific site or type being indicated by a modifying term.

connective tissue diseases - where the body's own immune system attacks its own connective tissue as being foreign. Among these diseases are scleroderma and SLE.

Systemic Lupus Erythematosis (SLE) - is a disease of unknown mechanism where the immune system attacks self cells. A hallmark of this disease is the presence of a number of antibodies to nuclear components, but other immunologic abnormalities exist as well. Some patients with SLE have spontaneous remission, others respond favorably to treatment with corticosteriods and in some patients the course is unresponsive to currently available treatments. Viral infections and genetic predisposition are considered possible etiologic factors of SLE.

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Blood

The 5 - 5.5L of blood in the human adult composes about 8% of the total body weight. Blood consists of

three types of cellular elements - erythrocytes, leukocytes, and platelets suspended in a liquid medium

known as plasma. Plasma is a complex liquid that acts as transport medium for substances being carried in

the blood. It also known as extra cellular fluid and is a liquid composed mainly of water, but also has a

small percentage of various organic substances such as plasma proteins and electrolytes.

I. Erythrocytes

Erythrocytes primarily transport oxygen in blood. An erythrocyte is essentially a membrane

bound sac full of hemoglobin and enzymes; it does not contain a nucleus, organelles, or

ribosomes. The omission of these substances allows the erythrocyte to maximize its interior space

for oxygen transport. The shape of the erythrocyte also allow it to perform its primary task with

greater efficiency - the healthy erythrocyte has a flat indented disc shape (see picture). The

flattened disc shape increases the surface area for oxygen diffusion compared to the surface area

available on a typical spherical shaped cell.

Erythrocytes contain hemoglobin (hgb) which bind and transport oxygen. Hgb is a complex

shaped molecule consisting of a globin (or protein) portion and a four-iron containing non-

proteinous nitrogenous groups known as "heme". Each of these four-iron atoms binds reversibly

to a molecule of oxygen. Hence, each hemoglobin molecule can carry four oxygen molecules. In

addition to transport of oxygen, hgb can also move carbon dioxide, H+ ions, and carbon monoxide

through the blood. Carbon monoxide is not normally present in blood, but if inhaled, it will

displace oxygen from the hgb molecule and take its place. This process will lead to carbon

monoxide poisoning if enough CO displaces O2 binding sites on hemoglobin.

Other facts to know about erythrocytes:

An average of 25 - 30 trillion red blood cells are normally streaming through your blood

vessels at one time. They are replaced by the bone marrow at a rate of 2 to 3 million cells per

second.

The life expectancy of an erythrocyte cell is only 120 days.

There are about 100 million hgb molecules within one erythrocyte.

As a RBC ages, its membrane becomes fragile and become prone to breakage as the cell

squeezes through tight spots such as small capillaries. New cells are produced in the bone

marrow to replace old ruptured cells. These processes occur at the rate of two to three million

cells per second.

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II. Platelets

Platelets are cell fragments shed off the outer edges of large bone marrow bound cells known as

megakaryocytes. Platelets lack nuclei, however, they are equipped with organelles and cytosolic

enzyme systems for generating energy and synthesizing of secretory products. Their primary

function is clot formation.

Other facts to know about platelets:

An average of 250,000,000 platelets are normally present in each milliliter of blood (range of

150,000 - 350,000/mm3).

Platelets have a life expectancy of 10 days. Unfunctional platelets are removed from the

blood circulation by white blood cells in the spleen and liver. They are replaced by new

platelets released from the bone marrow.

III. Leukocytes

Leukocytes are the mobile units of the immune system. They defend the body against invasion

against harmful organisms or substances known as pathogens. They also function to identify and

destroy cancer cells and act as a clean-up crew by destroying dead or injured cells (an essential

component of tissue repair). Leukocytes are present in the blood only while in transit from their

site of origin and storage in the bone marrow to their site of action in the tissues. At any given

time, the majority of the leukocytes are out in the tissues on surveillance missions or fighting

pathogens. All leukocytes have a limited life span and are replenished by ongoing production of

cells from the bone marrow.

Leukocytes lack hemoglobin and vary in structure and function. There are two main categories of

leukocytes: polymorphonuclear (many-shaped nucleus) granulocytes (granule-containing cells)

and mononuclear (one-shaped) agranulocytes (non granule-containing cells). There are three

types of granulocytes that can be differentiated upon the basis of the varying affinity of their

granules for dyes: eospinophils (have an affinity for the red dye eosin), basophils (take up a basic

blue dye), and neutrophils (are neutral, showing no dye preferance). Agranulocytes include

monocytes and lymphocytes. The total number and percentage of each of the different types of

leukocytes produced vary depending on the momentary defense needs of the body. The functions

of each of the leukocytes are listed below:

Polymorphonuclear granulocytes:

Neutrophils are important in engulfing bacteria and cell debris. They release

interleukin-1 (IL-1) in response to tissue injuries.

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Eosinophils specialize in attacking parasites and play a major role in allergic responses.

Eosinophils release substances from their granules that damage the parasitic membrane.

Basophils release two chemicals: histamine, which is important in allergic responses and

heparin, which helps to clear fat particles from the blood.

Agranular monocytes:

Monocytes reside in the tissues and mature to become the large tissue phagocytes known

as macrophages. Macrophages perform phagocytic activity.

Lymphocytes provide defense against bacteria, viruses, and other targets for which they

are specifically programmed. Their defense mechanisms include production of

antibodies and cell-mediated immune responses. B-lymphocytes produce antibodies

which circulate in blood. An antibody binds with and marks specific foreign matter such

as bacteria for destruction (by phagocytosis usually). T-lymphocytes do not produce

antibodies, rather they use an direct method to destroy specific target cells known as cell-

mediated immune response.

Summary of blood contents:Blood contains:42-45% RBC, <1% leukocytes and platelets, and 55 - 58% plasmaHematocrit: % of whole blood volume occupied by RBC's.

A typical blood count contains:

Erythrocytes (RBC) - 5,000,000,000 cells/ml of blood (5,000,000/mm3)Leukocytes (WBC) - 7,000,000 cells/ml of blood (7,000 mm3)Differential count: (percentage distribution of types of leukocytes)

Neutrophils 60-70% Lymphocytes 25-33%Eosinophils 1-4% Monocytes 2-6%Basophils .25 - .5%

Total platelets: 250,000,000/ml blood (250,000/mm3)

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VI. IMMUNE SYSTEM

The Immune system defends against foreign invaders and transformed body cells and sets the path

for tissue repair by removal of cellular debris.

A. Immunity

Immunity refers to the body's ability to resist and eliminate potentially harmful foreign

materials or abnormal cells. The immune system:

Defends against invading pathogens (disease-producing microorganisms)

Removes tissue debris and old-worn out cells.

Targets and destroys abnormal or mutant cells that originate within the body.

May launch an inappropriate immune response that either leads to allergies (when the

body turns against a normally harmless substance) or to autoimmune diseases (when the

immune system produces antibodies against the body's own "self" cells).

Protect the body against tissue cells from a foreign host (which, in some cases, may

induce organ transplantation rejection).

The primary microorganisms against which the immune system defends the body are viruses

and bacteria. Pathogenic bacteria invade the body and induce tissue damage by releasing

enzymes or toxins that physically injure or functionally disrupt affected cells and organs. The

disease producing power of a pathogen is called virulence. Viruses induce cellular damage by

causing the host cell to produce substances toxic to the host, transforming normal host cells

into cancer cells, and incorporating itself into the host cell resulting in the destruction of the

cell by the hosts own immune response.

1. Immune Responses: Non-specific and Specific Immune Responses

Immune responses may be either specific or non-specific. Non-specific immune responses

are inherent defense responses that non-selectively defend against foreign or abnormal

material of any type. Such responses are a fist line of defense against a wide range of

threatening factors. Specific immune responses, however, are selectively targeted against a

specific foreign matter to which the body has been previously exposed. These specific

responses are mediated by lymphocytes .

1. Non-Specific Responses

Non-specific responses occur regardless of previous exposure to a pathogen. The

following are various defenses that come into play with a non-specific immune

response:

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Inflammation - a response to tissue injury in which the phagocytes (neutrophils and

macrophages) play a major role. The primary goal of the inflammatory response is

to isolate, destroy, or inactivate invaders; remove cellular debris; and prepare for

healing and repair.

Interferon secretion - secretion of a family of proteins that defend against viral

infections.

Natural killer (NK) cells - a class of cells that spontaneously lyse and destroy virus-

infected host cells and cancer cells.

Complement system - a group of inactive plasma proteins that when activated, bring

about destruction of foreign cells by attacking their plasma membranes. For

example, when you cut your finger, it becomes red, tender and swollen. This is due

to to the release of complement. Complement are protective proteins that amplify

the inflammatory response.

2. Specific Immune Response

Upon initial exposure to a microbial invader, specific components of the immune

system become specially prepared to selectively attack the particular foreign agent.

The cells of the specific immune system, the lymphocytes are each equipped with

surface membrane receptors that are able to bind with only one specific complex

foreign agent, known as an antigen. The incredible variability in antigen-detecting

ability between different lymphocytes arises from the shuffling around of a few

different gene segments coupled with mutations, during lymphocyte development.

There are two broad classes of specific immune responses: antibody mediated

immunity and cell-mediated immunity. Both types of immune responses involve

binding of a lymphocyte with a specific antigen and consequent destruction of the

antigen. However, the effector cells, stimuli, and method of destruction are different

in these two types of immune responses. Plasma cells derived from B lymphocytes

(B-cells) are responsible for antibody-mediated immunity, whereas T lymphocytes

(T-cells) accomplish cell-mediated immunity.

A. Antibody mediated immunity & B-cells

The binding of a B-cell with an antigen induces the cell to differentiate into

plasma cells. Plasma cells produce antibodies against that specific antigen.

Antibodies are secreted into the blood and are now referred to as

immunoglobulins. Antibodies are grouped into the five subclasses based on

differences in their physiological activity:

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IgM - serves as the B-cell surface receptor for antigen attachment. It is secreted

during the early stages of plasma cell response.

IgG - the most abundant immunoglobulin in the blood. It proliferates when the

body is reintroduced to an antigen.

IgE - helps protect against parasites and is also the antibody mediator for

allergic responses such as hay fever and hives.

IgA - this type of immunoglobulin is found in the secretions of the digestive,

respiratory, and genitourinary systems. It is also found in breast milk and tears.

IgD - the function of this immunoglobulin is currently unknown.

It is important to note that the above five immunoglobulins are five functional subclasses

of immunoglobulins and within each subclass are millions of different antibodies - each

able to bind only to a specific antigen. Antibody proteins of these five subclasses are

composed of four interlinked polypeptide chains - two long heavy chains and two light

short chains arranged in the shape of a "Y" (see picture). Characteristics of the arm

region s of the Y determine with what antigen the antibody can bond (the specificity).

The tail portion of the antibody determines the functional properties of the antibody

(what the antibody does once bound to the antigen).

Antigen-antibody complexes causes various immunological defenses to come

into play:

Activation of complement system

Enhancement of phagocytosis

Stimulation of K (killer) cells

Some B cells will become antibody-secreting plasma cells. However, others will become

memory cells, which remain dormant until a person is exposed to the same antigen again.

Once this happens, the memory cells are primed and ready for a faster reaction compared

to the initial reaction: during initial contact with an antigen, the antibody response is

delayed until plasma cells can be formed and consequently the immune response does not

peak for a couple of days to weeks. This is called the primary response. If a person is

exposed to the same antigen, a more rapid and potent response known as a secondary

response is generated. This more powerful immune response is frequently sufficient to

prevent or minimize overt infection upon subsequent exposures to the same pathogen,

thus forming a long-term immunity against a specific disease. The original antigenic

exposure that induces memory cell formation can occur either by infection or through

vaccination. During vaccination, the individual is purposefully exposed to a pathogen

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devoid of its disease causing abilities (so that antibodies can be generated against the

pathogen without the person having the actual disease).

Primary response : Secondary response:slow onset rapid onsetlow magnitude high magnitude (more powerful)short lived response long lived responseIgM IgG (or IgA or IgE) predominantly

Cell mediated immunity & T-cells

T-cells must be in direct contact with their targets in order to destroy them,

known as cell-mediated immunity. T-cells release chemicals that destroy

targeted cells once in contact with them. Like B-cells, T-cells are antigen-

specific. There are 3 types of T- cells:

Cytotoxic T-cell (killer T cells or CD 8 cells) - these cells destroy host cells

bearing foreign antigens, such as body cells invaded by viruses or cancer cells.

Cytotoxic T cells as well as NK cells destroy a target cell by releasing perforin

molecules which penetrate the target cells membranes forming porelike channels

that allow unregulated entry of water and salts into the cells causing eventual

destruction. Cytotoxic T-cells also produce chemicals that cause apoptosis of

the target cell.

Helper T-cells (CD4 cells) - evoke the development of antigen-stimulated B

cells into antibody-secreting cells; enhance activity of appropriate cytotoxic and

suppressor T-cells; activate macrophages. Helper T-cells, unlike cytotoxic T-

cells do not directly eliminate target cells. Rather, helper T-cells secrete

chemicals that "help" or enhance activity of other cells of the immune system.

These cells are the most abundant of the T-cell types circulating in the blood.

Suppressor T-cells - Suppress both B and T-cell activity. They prevent

excessive immune reactions that might harm the body and probably also play a

key role in preventing the immune system from attacking self tissues, known as

tolerance.

B. Disorders of the Immune System

Autoimmune diseases occur when the immune system becomes overeager and erroneously turns

against self cells that it no longer recognizes and them tolerates as self. Lupus, a disease

characterized by production of antibodies against self cells and diabetes, where T-cells attack the

pancreatic cells responsible for generation of insulin, are two examples of autoimmune diseases.

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Immune complex diseases occur when the body tissues are accidentally destroyed as an

overabundance of antigen-antibody complexes activate excessive quantities of complement which

destroys surrounding normal cells as well as the antigen.

Allergies occur when the immune system inappropriately launches an attack on a harmless

material such as dust or pollen. There are specific IgE molecules for oak pollen and ragweed,

agents which contribute to hay fever, an allergic response.

Mechanism:

1. The initial exposure to an allergen evokes large amounts of IgE antibody release from the B-

cells.

2. The IgE attach to mast cells.

3. Upon and 2nd exposure to an allergen, the allergen binds to the IgE and triggers the mast cells

to release histamine that causes an allergic response (wheezing, runny nose, sneezing, itching,

watery eyes). Occasionally basophils and other WBC's may become involved in an allergic

response. This sometimes leads to an anaphylactic shock which is the sudden loss of blood

pressure and can be fatal. Allergy shots work by inducing the body to produce a vast amount

of IgG which out-competes and displaces the IgE antibodies located on IgE-mast cell

complexes.

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